Patent GB-1287001-A (GB)
Title: New semi-synthetic penicillin esters
Inventor: FREDERIKSEN ERLING KNUD
IPC: C07D499/00
Filed: 1969-03-18
Abstract: 1287001 #-Amino-α-arylethyl penicillin esters LOVENS KEMISKE FABRIK PRODUK. TIONSAKTIESELSKAB 10 March 1970 [18 March 1969 21 July 1969] 14218/69 and 36581/69 Headings C2A and C2C . Novel esters of 6-(α-aryl-#-amino-ethyl) penicillins having the Formula (I), (II) or (III) and salts thereof with non-toxic acids, wherein n is 0-5; R 1  to R 9  are each H, CF 3 , NO 2 , NH 2 , OH, halogen, alkyl, alkoxy, alkylthio, alkylsulphonyl, alkanoyl, alkanoylamino, mono- or dialkylamino, C 5 -C 7  cycloalkyl or cycloalkoxy, aryl, aralkyl, aralkoxy or aralkylthio, and R 2  withR 1  or R 3 , R 5  with R 4  or R 6 , and R 8 with R 7  or R 9  can complete a carbocyclic ring; B is -O-, -S-, or -NH-; and A is an aliphatic, alicyclic, aromatic or heterocyclic radical which may be substituted, are prepared either (a) by acylating the corresponding ester of 6-aminopenicillanic acid or a reactive derivative thereof with the appropriate α-aryl-#-substituted-ethyl carboxylic acid or its acylating derivative and if required, converting the #-substituent to -NH 2 ; or (b) by esterifying a 6-(α-aryl-#- amino - ethyl) - penicillanic acid or its salt, with a compound of Formula (VIII): wherein n and A are as above and X<SP>1</SP> is halogen, C 1 -C 16  acyloxy, or alkyl- or arylsulphonyl. The #-amino group may be protected during the reactions or may be replaced by a group (e.g. azido, nitro or halogen) which is subsequently convertible to -NH 2  by a method which does not cause destruction of the ester linkage or the lactam ring. The reactive derivative of the 6-amino-penicillanic acid may be an N-trialkylsilyl radical. Suitable acylating agents may be the acid halide, anhydride or mixed anhydride, or the free acid may be used in the presence of a condensing agent. Any hydroxy groups present are preferably also protected prior to the preparative reaction. In a modification of the process (b) an easily available 6- acylamino penicillanic acid is esterified, the 6-acyl group being subsequently split off and replaced by the α-aryl-#-amino-ethyl group of the inventive compound. D,L - # - amino - α - (4 - hydroxy phenyl) propionic acid is prepared by hydrolysing the corresponding 4-methoxy compound with aqueous HBr. The compound is then protected on the amino and hydroxy groups by treatment with carbobenzyloxy chloride. D,L -# - amino - α - (3 - chloro - 4 - hydroxyphenyl) propionic acid is prepared by halogenation of the corresponding unhalogenated acid using sulphuryl chloride. The amino group is then protected by treating the compound with carbobenzyloxy chloride. D,L - # - amino - α - (3 - aminophenyl) propionic acid is prepared by nitrating the phenyl group in D,L-#-amino-α-phenylpropionic acid and hydrogenating the 3-nitrophenyl compound. Both amino groups are then blocked by treatment with carbobenzyloxy chloride. # - Azido - α - phenyl propionyl chloride is prepared by halogenating the corresponding carboxylic acid with thionyl chloride. Pharmaceutical compositions comprise the penicillin of Formula (I), (II) or (III) above or non-toxic salts thereof together with a liquid or solid diluent or carrier.